The Impact of Chronic Pancreatitis on the Occurrences of Human Cancers: Real-World Data

Chronic pancreatitis (CP) may induce systemic inflammation, potentially increasing cancer susceptibility. However, the link between CP and extra-pancreatic cancer remains underexplored. Employing Taiwanese National Health Insurance Database data from 2000 to 2017, we compared 5394 CP patients with 21,576 non-CP individuals through propensity score matching. CP patients exhibited a significantly higher cancer risk (adjusted hazard ratio (aHR) of 1.32 for females and 1.68 for males) and cumulative incidence (p < 0.001) compared to non-CP individuals. CP showed notable associations with pancreatic (aHR = 3.51), liver (aHR = 1.62), stomach (aHR = 2.01), and other cancers (aHR = 2.09). In terms of liver cancer, CP was significantly associated with patients without viral hepatitis, regardless of gender (aHR = 2.01 for women; aHR = 1.54 for men). No significant cancer occurrences were observed within the first year following CP diagnosis. Pancreatic or liver cancer developed in approximately half of CP patients within 2–3 years, while gastric cancer in male CP patients predominantly occurred around the fifth year after diagnosis. These findings inform potential cancer-screening plans for CP patients.


Introduction
Chronic pancreatitis (CP) is a chronic inflammatory disease of the pancreas that could lead to irreversible damage to the pancreatic tissues and to associated exocrine and endocrine insufficiency [1][2][3][4][5]. The diagnosis of CP relies on a combination of image findings that indicate irreversible damage to the pancreas, such as calcification, stones, and duct stricture or dilation, along with manifested exocrine and endocrine dysfunctions [6].
Emerging evidence suggested that CP is not a localized disease confined to the pancreas [2]. CP is associated with elevated systemic levels of inflammatory mediators such as interleukin-6, tumor necrosis factor-α, interleukin-8, and members of the interleukin-1 family [7]. Systemic inflammation plays a significant role in the occurrence, staging, and progression of cancer [8]. Previous studies, albeit limited in sample size, have suggested a potential association between CP and the emergence of various extra-pancreatic cancers, comprising hepatic, pulmonary, colonic, and head and neck malignancies [9,10]. The association between CP, which is capable of inducing systemic inflammation, and cancer, a group of diseases associated with systemic inflammation, is thus intriguing and warrants further consideration. CP can often be attributed to several prevalent risk factors, including excessive alcohol consumption, smoking, and genetic mutation [2,[11][12][13]. Notably, alcohol use and smoking are well-established risk factors for various types of cancer. The shared risk factors, particularly alcohol and smoking, for CP and cancer provide additional grounds to consider the association between CP and cancer, in addition to the aforementioned factor of chronic inflammation.
This dual association underscores the intricate and multifaceted nature of the interplay between CP, smoking, alcohol, and the susceptibility to different forms of cancer. Despite the potential for CP to predispose individuals to systemic complications, the available realworld data concerning the association between CP and extra-pancreatic cancers are limited and inconclusive. This dearth of epidemiological data on CP in the large-sample-size general population, particularly within the Han ethnic group, contributes to the uncertainty. Ethnic variations and discrepancies in case definitions may lead to disparate findings. The rationale behind our study was to investigate the correlation between CP and the prevalence of different types of cancer within the Taiwanese population. We hypothesized that CP patients would exhibit an elevated incidence of extra-pancreatic cancers.

Materials and Methods
This study utilized the Longitudinal Generation Tracking Database (LGTD 2005), which was derived from the Taiwanese National Health Insurance Database (NHIRD). The NHIRD comprises data collected through the National Health Insurance (NHI) program, a nationwide initiative implemented in Taiwan in 1995 to enhance the country's healthcare and medical services. The LGTD encompasses demographic information of insured individuals, records of admissions and discharges, as well as medication and surgical procedure data for a randomly sampled population of 2 million Taiwanese individuals. To identify patients with cancer, we employed the linked registry of the Registry for Catastrophic Illness Patient Database (RCIPD), also derived from the NHIRD in Taiwan. Disease diagnoses were categorized utilizing the International Classification of Diseases, Ninth and Tenth Revision, and Clinical Modification (ICD-9-CM and ICD-10-CM) coding systems, as previously described in our published works [14][15][16][17][18][19][20][21][22][23][24][25]. Ethical approval for this study was obtained from the Institutional Review Board of the China Medical University Hospital Research Ethics Committee (CMUH109-REC2-031(CR-2)).
The study population included individuals aged 20 years or older but younger than 100 years of age, within the time frame of 1 January 2000, to 31 December 2017. These individuals were then categorized into two groups: those diagnosed with CP (identified by ICD-9 code 577.1 or ICD-10 code K86.1) and those without such a diagnosis. For patients diagnosed with CP, the index date was defined as the date of their initial CP diagnosis. For the control group, the index date was randomly assigned as the date when their follow-up period commenced after 1 January 2000. The two cohorts were matched based on sex, age (in 5-year intervals), year of the index date, Charlson Comorbidity Index (CCI), and NSAID (nonsteroidal anti-inflammatory drug) usage. Propensity score matching was employed with a 1:4 ratio. We excluded subjects who had a prior diagnosis of CP before the index date, individuals aged under 20 or above 100 years, those with missing sex or age data, and individuals with less than 1 year of follow-up time.
Categorical variables at baseline in different groups were evaluated using the chisquare test, whereas the means of continuous variables were compared using Student's t-test. Incidence rates were calculated per 1000 person-years. The hazard ratios (HR) and their corresponding 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression model to assess the risk between the two cohorts. Both unadjusted (crude) hazard ratios (cHR) and multivariable-adjusted hazard ratios (aHR) were calculated. Subdistribution hazard ratios (SHR) and 95% CIs were determined using the competing-risk regression model. Cumulative incidence curves were constructed using the Kaplan-Meier method, and differences between the two cohorts were assessed using the log-rank test. Statistical analyses were performed using SAS software, version 9.4, and plots were generated using R software, version 4.0. The level of statistical significance was set at p < 0.05.

Results
Following propensity score matching, a total of 26,970 subjects were included in this study, with 5394 being CP patients and 21,576 being non-CP subjects. Table 1 presents the baseline characteristics and demographics of the participants, including gender, age, CCI score, and medication usage. Both groups had a higher proportion of male participants compared to female participants. There were no statistically significant differences in the distribution of CCI scores and NSAIDs between CP patients and the control group. The mean follow-up time for CP patients was 3.27 (±1.72) years, while for those without CP, it was 6.22 (±3.56) years.   Figure 1 illustrates the cumulative incidence of cancer, which was significantly higher in the CP cohort compared to the non-CP cohort. PYs: person-years; IR: incidence rate; CI: confidence interval; cHR: crude hazard ratio; aHR: adjusted hazard ratio; aSHR: adjusted subdistribution hazard ratio; CCI score: Charlson comorbidity index score; NSAIDs: non-steroid anti-inflammatory drugs. Table 3 presents the risk of cancer in individuals with CP compared to those without CP, stratified by sex and age. In both female and male patients, CP patients exhibited a significantly higher risk of cancer compared to the non-CP group (female: aHR = 1.32; 95% CI = 1.05, 1.66/male: aHR = 1.68; 95% CI = 1.47, 1.92). This increased risk was consistently observed across all age groups, with the CP cohort demonstrating higher risks compared to the controls (20-39: aHR = 2.38; 95% CI = 1.77, 3.19/40-59: aHR = 1.63; 95% CI = 1.38, 1.92/≥60: aHR = 1.32; 95% CI = 1.09, 1.59). Furthermore, CP patients had a higher risk of developing cancer compared to non-CP patients, regardless of their CCI score (CCI = 0: aHR = 1.57; 95% CI = 1.34, 1.83/CCI = 1-2: aHR = 1.51; 95% CI = 1.24, 1.83/CCI ≥ 3: aHR = 1.77; 95% CI = 1.30, 2.41). Similarly, a significantly elevated risk of cancer was observed for the CP cohort compared to the controls, regardless of NSAID use (non-NSAIDs: aHR = 1.80; 95% CI = 1.50, 2.15/NSAIDs: aHR = 1.45; 95% CI = 1.25, 1.68). In other words, CP patients were consistently associated with a higher risk of cancer, irrespective of sex, age, CCI score, and NSAID exposure.         PYs: person-years; IR: incidence rate; cHR: crude hazard ratio; aHR: adjusted hazard ratio; CI: confidence interval. Figure 2 provides an overview of the temporal association between liver cancer, pancreatic cancer, stomach cancer, and other cancers, including nasopharyngeal cancer diagnoses, in patients with CP. Remarkably, no occurrences of these cancers were observed within the first year following a CP diagnosis in patients. Subsequently, among male and female CP patients who developed pancreatic cancer, as well as female CP patients who developed liver cancer, close to half of the patients experienced cancer onset within 2-3 years after the CP diagnosis. In male CP patients who developed gastric cancer, approximately half of the cases occurred during the fifth year following the CP diagnosis.  Timeline of liver cancer, pancreatic cancer, gastric cancer, and other cancers, including nasopharyngeal cancer, occurring within a ten-year follow-up period in CP patients. To comply with government data security regulations, patient information with values or differences below three has been excluded from the chart.

Discussion
Alcohol abuse and smoking are common risk factors shared by both CP and various types of cancer. Therefore, it is reasonable to make hypotheses about the potential association between CP and the development of human cancers. Our study revealed a significant correlation between CP and the development of various human cancers, Figure 2. Timeline of liver cancer, pancreatic cancer, gastric cancer, and other cancers, including nasopharyngeal cancer, occurring within a ten-year follow-up period in CP patients. To comply with government data security regulations, patient information with values or differences below three has been excluded from the chart.

Discussion
Alcohol abuse and smoking are common risk factors shared by both CP and various types of cancer. Therefore, it is reasonable to make hypotheses about the potential association between CP and the development of human cancers. Our study revealed a significant correlation between CP and the development of various human cancers, notably liver and stomach cancer. By leveraging a nationwide registry database and encompassing a substantial sample size, we conducted this investigation within the Taiwanese population, allowing us to gather robust real-world data pertaining to the impact of CP on cancer risk. The study employed a longitudinal design, spanning a 17-year period, and included a cohort of approximately 2,000,000 residents of Taiwan. The extended duration and large sample size ensured high statistical power and minimized selection bias. Notably, the NHI program covers over 99.9% of Taiwan's population, enhancing the generalizability of our findings to the entire populace. These findings offer compelling evidence that CP manifests systemic effects beyond its localized nature. Recognizing the public health implications, future research should concentrate on evaluating the efficacy of cancer screening protocols tailored specifically for CP patients. This discovery opens up promising avenues for cancer prevention strategies and carries significant implications for clinical practice and future research endeavors in this domain.
The precise mechanisms underlying the development of cancer in patients with CP remain unclear. Various potential mechanisms have been proposed, with systemic chronic inflammation emerging as a potential factor. CP represents an infectious process that, if not adequately addressed, can lead to systemic chronic inflammation. Inflammatory processes can generate free radicals and active oxidative/nitrosative intermediates, which could contribute to DNA mutations and interfere with DNA repair mechanisms within cells [26]. Moreover, inflammatory cells themselves may perpetuate the cycle by producing free radicals, cytokines, chemokines, and arachidonic acid metabolites, leading to the recruitment of more inflammatory cells [26]. Despite the demonstrated potential of specific anti-inflammatory drugs in preventing or mitigating the risk of certain cancers at different anatomical sites (e.g., colorectal, esophageal, gastric, biliary tract, and breast cancers), our study produced contrasting findings. One possible explanation for this discrepancy is that patients with higher CP severity may consume larger quantities of NSAIDs, thereby making NSAID exposure correlate with CP severity.
In our study, despite having only 41 cases of pancreatic cancer in our population, we observed a significant association between CP and pancreatic cancer in both sexes. This result is consistent with the findings of other studies conducted to date, indicating that CP is a risk factor for pancreatic cancer [27]. This further strengthens the credibility of our data.
Hepatitis B and C viruses have been shown to cause acute and chronic infections that lead to the development of hepatocellular carcinoma, which accounts for 90% of all liver cancer [28,29]. In our study, male CP patients without hepatitis B or C were found to have a higher risk of liver cancer. This discovery supports the notion that CP is an independent risk factor for liver cancer, which may be caused by the systemic inflammation associated with CP.
Some studies have shown no association between CP and stomach cancer; our study discovered a significant association between CP and stomach cancer. However, CP and stomach cancer share similar risk factors, such as alcohol use and smoking [30]. Our study failed to retrieve information concerning alcohol use and smoking. We hypothesize that the results might be different after modifying the factors of alcohol use and smoking.
In one Taiwanese population-based study, it was found that CP is a risk factor for head and neck cancer, and the risk increases with comorbidity [10]. In our study, we observed a comparable pattern and noted a more pronounced influence of CP on head and neck cancer (shown in "other" cancer). The differential outcomes between genders could potentially be explained by the existence of shared risk factors linking CP and head and neck cancer, which are more prevalent among Taiwanese males. Factors such as smoking, alcohol consumption, and betel nut chewing are more frequently observed in males within Taiwanese society and are recognized as established risk factors for head and neck cancer [31]. Table 6 provides a summary of the previous research that has investigated the association between CP and cancer. Two studies found that CP patients had a higher risk of liver cancer, which is consistent with our findings. One study indicated that the risk of liver cancer decreased after omitting liver cancer cases diagnosed within a year of admission for pancreatitis [32]. One possible explanation is that when patients are diagnosed with pancreatitis, concurrent liver cancer is also detected. Another cohort study by Agarwal S et al. examined the risk of pancreatic cancer among patients with different types of chronic pancreatitis, including alcoholic chronic pancreatitis (ACP), idiopathic juvenile chronic pancreatitis (IJCP), and idiopathic senile chronic pancreatitis (ISCP). The study found that ISCP was associated with a higher risk of pancreatic cancer [33].  Our study revealed that no significant occurrences of cancers were observed within the first year following CP diagnosis. Among CP patients who developed pancreatic cancer (both sexes) and female CP patients with liver cancer, nearly half experienced cancer onset within 2-3 years after the CP diagnosis. For male CP patients with gastric cancer, approximately half of the cases occurred during the fifth year after the CP diagnosis. Notably, the intensity of CP follow-up decreased over time in the clinical setting. Our study established that the "risk window" opens at least one year after CP diagnosis and persists for up to five years. Consequently, we recommend rigorous cancer screening for CP patients between one and five years after CP diagnosis. During the initial five years following the diagnosis of CP, it is imperative for both clinicians and patients to approach the condition with vigilance.
This study's primary limitation is the lack of lifestyle information in the utilized database, particularly concerning patients' alcohol consumption and smoking habits. However, it is noteworthy that lung cancer consistently exhibits the highest hazard ratio among smokers in different studies [42,43], and esophageal cancer is most strongly associated with alcohol consumption [44,45]. In our cohort, neither lung nor esophageal cancer showed a significant association with CP. Consequently, the observed CP-cancer association cannot be solely attributed to alcohol consumption or smoking. Moreover, important patient data, including genetic predisposition, family history, and environmental influences on tumor growth, were not available in NHIRD. Additionally, surveillance bias may influence our findings, as CP-diagnosed individuals often undergo regular monitoring, leading to increased exposure to cancer screenings and referrals, potentially impacting the observed outcomes. Our research design does not definitively elucidate the underlying mechanisms driving the CP-cancer association. In spite of these limitations, our study provides supportive evidence for a robust association between CP and human cancer. To gain a more comprehensive understanding, future studies should address these limitations and explore potential mechanistic links.

Conclusions
Our population-based cohort study demonstrated a significant correlation between CP and heightened susceptibility to specific types of cancer in humans, most notably liver, pancreatic, and stomach cancer. However, to establish a concrete association and gain deeper insights into the underlying pathogenesis linking CP to human cancer, further investigations in the form of randomized controlled prospective studies and clinical trials are imperative. The development of a screening program tailored to CP patients should be considered to enable the early detection of cancer. This proactive approach holds the potential to significantly improve patient outcomes. We firmly believe that our findings can contribute to the implementation of appropriate strategies for the follow-up care for CP patients, while also raising public awareness regarding the heightened cancer risk associated with this condition.

Data Availability Statement:
The data presented in this study are available on request from the corresponding author.